HTLV-III/LAV, the virus recently identified as the causative agent of AIDS, has been molecularly cloned and sequenced, its major genes identified, and its identity as a novel human retrovirus related to the lentivirus family confirmed. It has recently been discovered that striking variation is present within the envelope genes of different HTLV-III/LAV isolates and it has been postulated that this envelope variations may be intimately involved in the mechanisms by which the virus evades host immune defenses causing persistant and fatal infection. It has also been speculated that envelope variation may influence tissue tropism and virulence of the virus. This project proposes to define, at the nucleotide sequence level, the spectrum and nature of envelope variation in HTLV-III/LAV viruses and to evaluate the biologic importance of these changes. The first phase of the project will employ Southern blot hybridization, molecular cloning, and nucleotide sequencing of well-defined HTLV-III/LAV isolates from African, Haitian, European, and American patients with AIDS or AIDS-related complex (ARC) as well as virus isolates from donor-recipient pairs and from the same patient over time (i.e., sequential virus isolates over a 3-24 month period). The following questions, in particular, will be addressed: 1) What is the extent of nucleotide sequence diversity in different HTLV-III/LAV isolates from the same and different geographic regions and do genomic patterns emerge which reveal the virus's evolution and geographic migration? 2) What is the precise nature and extent of viral envelope gene variation? 3) Does the HTLV-III/LAV genome change in vivo within the lifetime of the host, in response to selective immune pressures? 4) Do immunologic or non-immunologic pressures unique to each infected patient select for envelope variation as the virus is transmitted from person to person? 5) Do genetically-distinct subtypes of HTLV-III/LAV exist which differ in virulence, cytopathicity, and/or tissue tropism? The second phase of the project will make use of the molecular clones and nucleotide sequence information obtained in phase one to evaluate the effects of envelope variation on critical viral properties, including cytopathicity, syncytia formation, and tissue tropism. These studies will utilize transfection, eukaryotic gene expression, and synthetic peptides to evaluate specific gene functions.